Breast cancer is the most common cancer among women in the United States. It is the second leading cause of cancer death in women. The American Cancer Society estimates about 232,670 new cases of invasive breast cancer in 2014 and ~ 40,000 women will die from breast cancer this year. Despite the use of adjuvant endocrine treatment, prognosis remains poor for a significant population of patients. One of the approaches to control cancer could be its prevention by diet, which inhibit one or more neoplastic events and reduce the cancer risk. Cancer prevention by the use of naturally occurring dietary substances is considered a practical approach to reduce the incidence of cancer. Bitter melon (Momordica charantia) is widely cultivated in Asia, Africa, and South America and extensively used in folk medicines as a remedy for diabetes. We have observed an anti-proliferative effect of bitter melon extract (BME) in a number of breast cancer cell lines in vitro. BME mediated breast cancer cell killing is associated with enhanced expression of p53, p21, and pChk1/2, and decreased expression of cyclin B1 and cyclin D1. More evidence support the importance of the tumor microenvironment (TME) in cancer development and progression where other cell types (such as immune cells) cross-talk with tumor cells. Naturally occurring anti-inflammatory or immunomodulatory plant extracts contribute to an anticancer effect by modulation of immune signaling pathways. However, the role of BME as an immunomodulator in breast cancer has not been studied. Based upon our in vitro data, we hypothesize that BME has chemopreventive activity against breast cancer growth by activating NK cell activity and inhibiting immunosuppressive T cell (Treg) function. In this R21 exploratory grant application, we will explore the preventive potential of BME against breast cancer and its novel mechanism as an immune modulator in the tumor microenvironment. Together, our proposed work will hold promise to advance our understanding of breast cancer disease prevention and may open up new avenues for additional treatment strategies.